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Chapter 41
Oral Cavity Cancer
Rafael R. Mañon
Jeffrey N. Myers
Deepak Khuntia
Paul M. Harari
The oral cavity consists of the lips, oral tongue, floor of mouth, retromolar trigone, alveolar ridge, buccal mucosa, and hard palate (Figs. 41.1, 41.2 and 41.3). Cancer of the oral cavity comprises approximately 30% of head and neck region tumors and 3% of all cancers in the United States (46). On the order of 31,000 new cases of oral cavity and oropharynx cancer were diagnosed in the United States in 2006 (104). Worldwide, head and neck cancer is the sixth most common malignancy, with over 274,000 new oral cavity cancers diagnosed annually (104). For all stages combined, the 5-year relative survival rate is 59% and the 10-year survival rate is 44% (104). Mortality rates for oral and pharyngeal cancers have shown a gradual decrease in the United States since the 1980s based on data from the World Health Organization (WHO) (111). One of the major prognostic factors for oral cavity cancer is the presence of lymph node metastases. The 5-year cancer-specific survival can be as high as 70% to 90% for patients without lymph node metastasis but drops by half for patients with node-positive disease (52). Worldwide, oral cancer is a substantial public health problem as one of the leading causes of cancer death in parts of Asia and Europe.
In the United States oral cavity cancer is predominantly a disease of older males. The disease is associated with the consumption of tobacco and alcohol (30). However, this trend is evolving as the prevalence of tobacco use in women increases (20). Recently, there has been some increase in the incidence of tongue carcinoma in younger nonsmokers and nondrinkers in the United States. The squamous lining of the oral cavity is composed of relatively thick mucosa with a keratin layer. However, the floor of mouth and ventral and lateral tongue possess a thinner mucosa with less surface keratin, potentially contributing to the higher incidence of cancer in these subsites (73).
A variety of distinct histologic types of cancer can arise in the oral cavity. The majority of these (95%) are squamous-cell carcinomas (45). The second most common histologic type derives from minor salivary gland rests. Other nonepithelial tumors such as melanoma, lymphoma, sarcoma, and ameloblastoma may also arise in the oral cavity, but are relatively uncommon in absolute numbers. Classification of tumors by subsite is useful because patterns of spread and clinical outcomes vary by specific subsite, partly reflecting the variable risk of nodal spread by anatomic site of presentation.
Anatomy
Lip
The lips begin at the junction of the vermilion border with the skin and form the anterior aspect of the oral vestibule. The lips are comprised of the vermilion surface, which is the portion of the lip that comes in contact with the opposing lip. The lips are well defined into an upper and lower. The primary motor control of the lips is provided by the buccal and mandibular branches of the facial nerve.
Oral Tongue
The anterior two thirds of the tongue is mobile and considered part of the oral cavity. The oral tongue extends anteriorly from the circumvallate papillae to the undersurface of the tongue at the junction of the floor of mouth. The fibrous septum divides the tongue into right and left halves. The oral tongue can be demarcated into four anatomic areas: the tip, lateral borders, dorsal surface, and undersurface (ventral surface). There are six pairs of muscles that form the oral tongue. Three of these muscles are extrinsic, while the other three are intrinsic. The extrinsic muscles include the genioglossus, hyoglossus, and styloglossus. The intrinsic muscles include the lingual, vertical, and transverse muscles. The former primarily move the body of the tongue, while the latter alter the shape and conformation of the tongue during speech and swallowing. The blood supply to the tongue is primarily via the lingual artery, tonsillar branch of the facial artery, and the ascending pharyngeal artery with primary drainage by the internal jugular vein. General sensation of the anterior two thirds of the tongue is supplied by the lingual nerve. Excluding the circumvallate papillae, taste fibers from the anterior two thirds of the tongue run in the chorda tympani branch of the facial nerve; the glossopharyngeal nerve provides sensation and taste to the posterior third of the tongue and circumvallate papillae.
Floor of the Mouth
The floor of the mouth is a semilunar space extending from the lower alveolar ridge to the undersurface of the tongue. The floor of the mouth overlies the mylohyoid and hyoglossus muscles. The posterior boundary of the floor of the mouth is the base of the anterior tonsillar pillar. This region is divided into right and left by the frenulum of the tongue and contains the ostia of the submandibular and sublingual salivary glands. A sling formed by the mylohyoid muscles medially supports the anterior floor of the mouth, and the hyoglossus supports the posterior floor of the mouth. The lingual and hypoglossal nerves are lateral to the hyoglossus, while the lingual artery is medial to the hyoglossus. Innervation of the floor of the mouth is provided by the lingual nerve.
Hard Palate
The hard palate extends from the inner surface of the superior alveolar ridge to the posterior edge of the palatine bone. This is a semilunar area between the superior alveolar ridge and the mucous membrane covering the palatine process of the maxillary palatine bones.
Alveolar Ridge
The alveolar ridges include the alveolar processes of the maxilla and mandible and the overlying mucosa. The mucosal covering of the lower alveolar ridge extends from the line of attachment of mucosa in the buccal gutter to the line of free mucosa of the
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floor of mouth. The lower alveolar ridge extends to the ascending ramus of the mandible posteriorly. The superior alveolar ridge mucosa extends from the line of attachment of mucosa in the upper gingival buccal gutter to the junction of the hard palate. The posterior margin is the upper end of the pterygopalatine arch.
Retromolar Trigone
The retromolar trigone is the triangular area overlying the ascending ramus of the mandible. The base of the triangle is formed by the posterior most molar, and the apex lies at the maxillary tuberosity.
Buccal Mucosa
The buccal mucosa includes the mucosal surfaces of the cheek and lips from the line of contact of the opposing lips to the pterygomandibular raphe posteriorly. This extends to the line of attachment of the mucosa of the upper and lower alveolar ridge superiorly and inferiorly. Innervation is supplied by the buccal nerve, a branch of the mandibular nerve.
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Epidemiology
Oral cavity tumors comprise roughly 30% of all head and neck cancers. The epidemiology of oral cancer strongly reflects exposure to certain environmental agents, particularly tobacco and alcohol. Worldwide, the incidence of oral cancer varies considerably. The age-adjusted world incidence for cancer of the oral cavity and pharynx is 8.3 per 100,000, but varies greatly with respect to age and sex (17). In Western Europe and Australia the incidence of oral cavity cancer closely approximates that of the United States. The incidence of cancer among males is highest in northern France, southern India, a few regions of central and Eastern Europe, and Latin America (69). Among women, the highest incidence is observed in India (40). The elevated rates of oral cavity cancer in France and Eastern Europe have been linked to the high rates of alcohol consumption in these countries.
A review of studies conducted between 1994 and 2001 indicates a strong causal relationship between smoking and cancer of the oral cavity (9,56,65). Smoking is identified as an independent risk factor in 80% to 90% of patients who present with cancer of the oral cavity (9,56,65). Cessation of smoking is associated with a decline in the risk of cancer of the oral cavity. Abstaining from the use of cigarettes resulted in a 30% reduction in the risk of cancer in those quitting from 1 to 9 years and a 50% reduction in those who quit for more than 9 years (65). In India the habit of chewing betel nut leaves rolled with lime and tobacco (mixture known as “pan”), which results in prolonged carcinogen exposure to the oral mucosa, is thought to be the leading cause of oral cancer (82,98). The practice of “reverse smoking” (smoking with the lighted end of the cigar in the mouth, also known as Chutta), peculiar to certain parts of India, is associated with increase in cancer of the hard palate (89). Although alcohol and tobacco have a synergistic effect on carcinogenesis, alcohol consumption may be an independent factor in the etiology of oral cavity cancer. Surveys of census-based population data in England and Wales suggest that the association between alcohol consumption and oral cavity cancer in males may be greater than that observed for cigarette smoking (49).
In the United States, cancer of the oral cavity afflicts older patients more than younger patients, and is three times more frequent in men than women (18). The incidence and mortality
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rates are higher for African American men (99). The mortality rates for African American males with oral or pharyngeal cancer is 7.5/100,000, nearly double that of Caucasians (3.9/100,000) (104). The survival rates are 61% in whites versus 39% in African Americans. Recent studies suggest that there may be a rising incidence in cancer of the tongue and mouth in young adults (80). Studies reveal that 4% to 6% of oral cancers now occur at ages younger than 40 years (63). Reports examining risk factors for oral cancer in the young provide evidence that many younger patients have never smoked or consumed alcohol; predisposition to genetic instability has been hypothesized as a causative factor (63).
Ultraviolet radiation has been associated with carcinoma of the lip. In geographic regions where there are long daily periods of sun exposure, cancer of the lip may represent up to 60% of all cancers of the oral cavity (4). Herpes simplex virus (HSV) and human papilloma virus (HPV) have also been implicated in the etiology of oral cavity cancer. The former has been shown to act as a cocarcinogen with tobacco and ultraviolet light in animal models (12,57). HPV-6 and -16 are the most common types of HPV associated with cancer of the oral cavity (79). HPV-16 is found two and five times more likely in precancerous oral mucosa and cancer in the oral cavity respectively, compared to normal mucosa (72). In males, HPV-16 confers a threefold risk of developing oral cavity cancer (66). Despite the fact that studies have detected high-risk HPV in nearly 50% of cases of oral cavity cancer, it is still uncertain whether infection with the virus is sufficient to promote development of oral cavity cancer (79).
Certain syndromes such as Plummer-Vinson (characterized by iron-deficiency anemia, hypopharyngeal webs, weight loss, and dysphagia) have been associated with oral cavity cancer. However, Plummer-Vinson syndrome is rare and accounts for a small number of cancers of the oral cavity. Disorders such as xeroderma pigmentosum, ataxia telangiectasia, Bloom syndrome, and Fanconi's anemia are a result of defective “caretaker” genes. Because such defects result in genetic instability, an increased incidence of second primary malignancies, including oral cancer, has been reported (88). By contrast, with the exception of Li Fraumeni syndrome, abnormalities in “gatekeeper” genes, which inhibit cell proliferation and/or promote cell death, do not appear to predispose to oral cancer. However, despite such reports, the genetics of oral cavity cancer have not been well delineated (18).
In patients with cancer of the oral cavity the risk of developing a second primary cancer is well recognized. The concept of field cancerization described by Slaughter and Smejkal (102) in 1953 and Day et al. (25) may explain the significantly higher
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rate of second malignancy in patients with head and neck cancers compared to the general population. In an analysis of 851 patients with squamous cell carcinoma of the head and neck, 19% of the study population developed a secondary head and neck carcinoma 5 years after undergoing initial therapy (95). The probability of developing a second metachronous malignancy at 5 years was 22% (18% for the subset of patients with oral cavity cancer) (95). Day and Blot (24) evaluated the risks of subsequent malignancies in 21,371 patients with oral and pharyngeal cancers between 1973 and 1987. The rate of development of second tumors was 3.7% per year. The risk of second primary cancer was 2.8 times greater than expected, with 20-fold increases of oral or esophageal cancers and fourfold to sevenfold increases of respiratory cancers. Crosher and McIlroy (22), in an analysis of the Scottish Cancer registry, found the overall risk of second cancers in patients with carcinoma of the oral cavity was 2.03 (95% confidence intervals 1.8 to 2.4) times greater than expected in the general population. In a meta-analysis patients with carcinoma of the oral cavity had the highest rate of second primaries, most of which occurred in the upper aerodigestive tract (51). Second primary cancers have an adverse effect on prognosis and are the major cause of treatment failure in patients with early stage disease (62,95).
Molecular Biology
In parallel to the Fearon and Vogelstein (37) model describing the genetic basis of colon cancer, there are a series of specific genetic events that precede the development of oral squamous cell carcinoma (16,47). Cancer progression models describe several steps that occur during tumor development: oncogenes become activated and tumor suppressor genes become deactivated and a series of these alterations are required for carcinogenesis. In the oral mucosa this genetic progression is reflected histologically by the transformation from normal mucosa to dysplastic epithelium and ultimately to a frankly invasive squamous-cell carcinoma. Data to support this model come from studies that reveal genetic alterations in histologically normal tissues and in premalignant lesions, including loss of heterozygosity at chromosomes 3p14 and 9p21. Furthermore, mutations in the region of chromosome 17p13, which encompass the tumor suppressor gene p53, are among the early events that contribute to malignant transformation. Indeed, biopsies of normal mucosa from patients with upper aerodigestive tract carcinomas frequently harbor p53 mutations. The accumulation of specific mutations contribute to changes in critical cellular processes that regulate growth, survival, immortality, tissue invasion, and new blood vessel formation, leading to changes in the biology of epithelial cells to the point where they acquire distinct histological characteristics. Why the same environmental exposure leads to tumor development in some individuals and not others may be explained in part by genetic susceptibility to tobacco carcinogens (59). This susceptibility has been linked to the ability to metabolize and break down carcinogens and/or repair damage to their DNA caused by the mutagens in tobacco.
Natural History and Patterns of Spread
Premalignant Lesions
Leukoplakia
Leukoplakia and erythroplakia are gross clinical descriptors that do not always correspond directly to specific pathologic entities (18,77). The WHO defines leukoplakia as a white patch or plaque that cannot be rubbed off or characterized clinically or pathologically as any other disease (77) (Fig. 41.4). Leukoplakia is not related to the presence or absence of dysplasia; however, it is the most common precursor of cancer of the oral cavity. Leukoplakia has a varied clinical appearance, and its appearance frequently changes over time. This is primarily a clinical entity, with certain key pathologic features. These features include hyperkeratosis and acanthosis. Leukoplakias begin as thin gray or gray/white plaques that may appear somewhat translucent, are sometimes fissured or wrinkled, and are typically soft and flat. They frequently have sharply demarcated borders but occasionally blend gradually into normal surrounding mucosa.
Homogenous leukoplakia is a uniform white lesion that is prevalent in the buccal mucosa. These lesions represent the most common variety of leukoplakia and have a low malignant potential. Conversely, high-risk oral leukoplakia demonstrates abnormal orientation of cells, nuclear hyperchromatism, increased mitosis, and nuclear cytoplasmic ratio (18). Clinically these lesions are nonhomogenous, nodular, speckled, or verrucous, with central ulceration or erosion (77,79). Follow-up studies demonstrate that between <1% to 18% of oral leukoplakias develop into oral cancer, with the latter clinical subtype conferring a higher risk of malignant transformation (54,90).
The natural history of leukoplakia is variable. Leukoplakia may regress spontaneously without therapy. A baseline biopsy can be performed to establish diagnosis and rule-out malignant transformation. Leukoplakia with clinically or histologically aggressive features, demonstrating dysplasia, should be excised.
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Erythroplakia
The term erythroplakia describes a chronic, red, generally asymptomatic lesion or patch on the mucosal surface that cannot be attributed to a traumatic, vascular, or inflammatory cause. Erythroplakia, like leukoplakia, is a clinical diagnosis of exclusion that requires the clinician to rule out all other erythematous oral lesions (96). However, erythroplakia is associated with a higher risk of malignant transformation than leukoplakia. Transformation rates are considered to be the highest among all precancerous oral lesions and conditions (91). Histopathologically it has been documented that in homogenous oral erythroplakia, 51% showed invasive carcinoma, 40% carcinoma in situ, and 9% mild or moderate dysplasia (91). The treatment of choice for erythroplakia is surgical excision.
Oral Cavity Cancer
Relative Distribution
The most common subsite for squamous-cell carcinoma of the oral cavity (excluding the lip) is the oral tongue (Fig. 41.5). In a review of 3,308 cases of oral cavity cancer treated at the University of Texas M.D. Anderson Cancer Center between 1970 and 1999, 32% were located in the oral tongue (18). The floor of the mouth is the second most common subsite where oral cavity carcinomas may arise. Carcinoma of the alveolar ridge accounts for approximately 10% of oral cavity carcinomas. Squamous-cell carcinoma of the retromolar trigone and hard palate is rare. Similarly, carcinoma of the buccal mucosa is rare in the United States, but is the most common carcinoma of the oral cavity in Southeast Asia because of the widespread use of betel nut (18).
Patterns of Spread
Local Spread
Carcinoma from distinct anatomic subsites may exhibit different tendencies for spread based on natural anatomic barriers and location. For instance, the majority of lip cancers are local growths that do not invade deeply into the tissues of the oral cavity or mandible (121). However, a select few lip carcinomas may be deeply invasive with perineural involvement, posterior spread to involve cortical bone, extension to the inferior alveolar nerve, or spread to the skin of the face (Fig. 41.6). Squamous-cell carcinoma of the floor of the mouth can secondarily involve the ventral tongue, extend along the lingual nerve, submandibular duct, or invade the cortex of the mandible. Tumors in this location can invade deeply, involving the muscles of the floor of the mouth. There is an anatomical gap between the mylohyoid and hyoglossus muscles through which a carcinoma can gain access to submandibular and sublingual areas. Carcinomas of the alveolar ridge and retromolar trigone tend to invade bone early. Tumors of the inferior alveolar ridge may access the mandibular canal and the inferior alveolar nerve, while tumors of the superior alveolar ridge may pass into the maxillary antrum or floor of the nose. Infiltrating lesions of the buccal mucosa can invade the buccinator muscle, extend to the buccal fat pad, and invade the subcutaneous tissue. The hard palate has a relatively dense mucoperiosteum that is relatively resistant to tumor invasion. However, the primary and secondary palates are fused at the incisive fossa, where tumors can gain access into the nasal cavity. The greater palatine foramina can allow tumors to spread posteriorly and enter the pterygopalatine fossa and skull base.
Lymphatic Metastases
For the purpose of staging and treatment planning, the neck is generally divided into five primary levels. Level I includes the submental and submandibular triangles. Level II includes the upper jugular chain lymph nodes from the base of skull to the carotid bifurcation and from the sternohyoid muscle anteriorly to the posterior border of the sternocleidomastoid posteriorly. Level III includes the mid-jugular nodes, which extend from the carotid bifurcation to the omohyoid muscle inferiorly, the sternohyoid medially, and the posterior aspect of the sternocleidomastoid posteriorly. Level IV includes the inferior jugular nodes, bounded by the omohyoid muscle superiorly, the clavicle inferiorly, and the posterior aspect of the sternocleidomastoid posteriorly. Level V includes nodes in the posterior triangle, bordered by the base of the skull superiorly, clavicle inferiorly, and posterior aspect of the sternocleidomastoid anteriorly.
The oral cavity has an extensive group of lymphatics that manifest a fairly predictable lymph node drainage pattern based on location (subsite) within the oral cavity (14) (Table 41.1). The upper and lower lip demonstrate distinct patterns of lymphatic drainage. The principal lymphatic drainage of the upper lip is to preauricular, periparotid, submental, and submandibular
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lymph nodes (level I), which secondarily drain to deep jugular lymph nodes. The medial portion of the lower lip drains primarily to the submental lymph nodes (level Ia), while the lateral portion drains to the submandibular triangle (level Ib).
A classical study by Lindberg (61) demonstrated that the superior deep jugular nodes are most frequently involved by cancers of the oral cavity. The oral tongue has an extensive lymphatic drainage. The anterior portion of the tongue drains to the submental nodes, and the lateral portion drains to the submandibular and deep jugular nodes (level Ia/Ib and level II). The posterior oral tongue drains into the upper jugulodigastric group of lymph nodes (level II). The lymphatics of the oral tongue also have extensive communication across midline; thus carcinomas of the oral tongue can metastasize bilaterally. Studies suggest that some carcinomas of the lateral oral tongue may metastasize to level IV lymph nodes without involving levels I, II, or III (13). This implies that there may be separate lymphatic channels draining from the oral tongue directly to level IV nodes, allowing for apparent “skip metastases.”
Dye injection studies have shown that the floor of the mouth has superficial and deep lymphatic drainage systems (13). The superficial system crosses randomly in the midline and drains into both the ipsilateral and contralateral submandibular lymph nodes (level I). The deep lymphatic system is thought to penetrate the periosteum and drains into the submandibular and upper jugular lymph nodes. Lymphatics from the buccal mucosa drain into the periparotid, submental, and submandibular nodes (level I). Tumors of the alveolar ridge may drain into the submental and submandibular triangles, upper deep jugular, and retropharyngeal lymph nodes. Tumors of the inferior alveolus are more likely to metastasize to the neck than tumors of the superior alveolus. The main lymphatic drainage from the retromolar trigone is into the superior-deep jugular lymph nodes (level II); however, there may be some drainage into periparotid and retropharyngeal lymph nodes. Lymphatics in the hard palate are few, but drainage is into submandibular (level I), superior deep jugular (level II), and retropharyngeal nodes.
The risk of neck metastases depends on several factors including site and size of the primary tumor. Overall, for patients with squamous-cell carcinoma of the oral cavity, cervical metastases occur in approximately 30% of cases (79). The rate of neck metastases for carcinoma of the lip is nearly 10% (79). Squamous-cell cancer of the oral tongue carries the highest risk of nodal metastases. The frequency of neck metastases can range from 15% to 75%, depending on the size of the primary lesion (61,109). Approximately 25% of patients with carcinoma of the oral cavity will have occult nodal metastases, and 3% of patients will have contralateral metastases (61,109). Contralateral metastases are more common in tumors that approach or cross the midline. Early tumors of the floor of the mouth have approximately a 12% to 30% incidence of occult nodal metastases depending on the thickness of the lesion, while larger lesions can have an incidence of nearly 50% (106). Approximately 15% to 20% of upper alveolar ridge tumors will involve the neck at presentation; the risk of occult metastases in a clinically negative neck is approximately 15% to 20% (61). The incidence of neck metastases in lower alveolar ridge tumors is higher than for tumors of the upper alveolar ridge (61). For cancers of the buccal mucosa, the incidence of positive cervical lymph nodes at diagnosis is 10% to 30%; the incidence of pathologically positive nodes in a clinically negative neck is about 15%. Similar rates of occult metastases occur for squamous-cell carcinoma of the retromolar trigone; however, patients tend to present with more advanced disease, resulting in a somewhat higher rate of regional metastases (79). The incidence of lymph node involvement from carcinoma of the hard palate is low, approximately 15% (100,121).
Distant Metastases
The majority of oral cavity cancers present as localized disease and remain localized until late in the course of their development. Distant metastasis occurs in approximately 15% to 20% of patients who eventually die of their disease (79). The risk of distant metastases increases with the degree of lymph node involvement. Patients with recurrent disease are also at higher risk for distant metastases (70). Patients without clinically appreciable neck disease rarely fail distantly after treatment. In general terms with respect to head and neck cancer, 66% of distant metastasis are to the lungs, 22% to the bones, and 9.5% to the liver (38). On rare occasion, the oral cavity will serve as a site for distant metastasis from another anatomic primary tumor site (Fig. 41.7).
Pathologic Classification
The predominant histopathologic type of cancer in the oral cavity is squamous-cell carcinoma. There are several variants of squamous-cell carcinoma, including basaloid squamous-cell carcinoma and verrucous squamous-cell carcinoma. Basaloid squamous-cell carcinoma is believed to have a worse prognosis than traditional squamous-cell carcinoma. In a retrospective comparison between basaloid squamous-cell carcinoma and traditional poorly differentiated squamous-cell carcinoma, the former had a higher incidence of advanced disease at presentation, distant metastases, and poorer overall survival rate (128). Verrucous carcinoma is an uncommon variant of squamous-cell carcinoma. It is generally considered a low-grade malignancy
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with low metastatic potential and good overall prognosis (18). For these reasons adjuvant radiation and elective neck dissection are often not indicated. Sarcomatoid carcinomas can be found in the oral cavity and larynx. This variant of squamous-cell carcinoma carries a poor prognosis with a mean survival of approximately 2 years (33).
Less than 10% of neoplasms of the oral cavity have nonsquamous histology. Most of these are minor salivary gland tumors, which tend to arise in the hard palate. Adenoid cystic carcinoma accounts for approximately 30% to 40% of minor salivary gland cancers of the oral cavity (126). Other histologies that can occur in the oral cavity include adenocarcinomas, melanoma, ameloblastoma, lymphoma, and Kaposi's sarcoma (Fig. 41.8). Approximately 50% of acquired im-munodefiency syndrome–related cases of Kaposi's sarcoma have oral cavity involvement (79). Most lymphomas in the head and neck arise in Waldeyer's ring (tonsil, base of tongue, and nasopharynx). Only 2% of all lymphomas are found in the oral cavity (41). Fortunately, melanoma of the oral cavity is very rare and represents only 0.2% to 8% of all melanomas (103). Mucosal melanomas generally have a worse prognosis than cutaneous melanomas.
Clinical Presentation
The oral cavity is an anatomic region that is readily accessible to visual inspection and palpation. Despite this fact, many patients with oral cavity tumors present with advanced stage disease as initial symptoms may be vague and painless. Tumors of the oral tongue often present as small ulcers and gradually invade the musculature of the tongue. Advanced lesions may be either ulcerative or exophytic and are usually quite evident. Some cancers of the oral tongue are painful even in their early stages. Cervical metastases occur early in the natural history of the disease, with 30% to 40% of patients harboring cervical lymph node metastases at diagnosis. Squamous-cell carcinomas of the oral tongue most often arise along the lateral borders of the tongue (18) (Fig. 41.9).
Lesions of the floor of the mouth are often infiltrative and may invade bone, the muscles of the floor of the mouth, and the tongue. The frenulum is frequently a site of involvement. Clinical fixation of the tumor to the mandible suggests periosteal involvement, which may occur early.
Tumors of the alveolar ridge may present with pain while chewing, loose teeth, or ill-fitting dentures in edentulous patients. These cancers often arise in edentulous areas or along the free margin of the mandibular alveolus (Figs. 41.10 and 41.11). Anesthesia of the lower lip and teeth may indicate involvement of the mandibular canal and inferior alveolar nerve.
Tumors involving the retromolar trigone region may present with an exophytic growth pattern and limited involvement of underlying bone (Fig. 41.12), or they may infiltrate cortical bone and spread along regional tissue planes to involve the pterygoid complex and parapharyngeal space. These latter lesions often induce trismus early in the clinical course.
Carcinoma of the buccal mucosa is rarely symptomatic early in its course. Lesions may be papillary or erosive and located near the dental occlusal line. These tumors are often relatively asymptotic and therefore seldom come to medical attention as T1 lesions. Often, these tumors manifest associated leukoplakia. Multiple primary sites and local recurrence are also common. These tumors most frequently arise adjacent to the lower molars along the occlusal line of the teeth.
Carcinoma of the hard palate is often painless, and the sole presenting symptom may be an irregularity in the mucosa or ill-fitting dentures. Other presenting symptoms include nonhealing ulcers of the hard palate, intermittent bleeding, and pain.
Diagnostic Evaluation
Patients with oral cavity cancer should undergo a comprehensive history and physical examination. Detailed examination is particularly important for oral cavity tumors in that much
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can be learned about cancers that afford opportunity for direct visual inspection and digital palpation. A biopsy of lesions in question should be obtained as well as a thorough dental assessment. Computed tomography (CT) scans, panoramic radiographs, magnetic resonance imaging (MRI), and other imaging studies may also be important for accurate staging of the tumor and in treatment planning.
The history of present illness should address the following issues: tobacco and alcohol use; dysphagia; odynophagia; pain; trismus; difficulties with speech; hoarseness; loose teeth; ill-fitting dentures; hypoesthesia in the lips or mandible; weight loss; and malnutrition. Otalgia suggests involvement of the ninth or tenth cranial nerve. Hypoesthesia usually results from perineural invasion, often from penetration of the mandible and perineural spread along the inferior alveolar nerve. The presence of trismus may indicate extension into the pterygoid musculature, signifying locally advanced disease. Other symptoms include a persistent ulcer, bleeding, drooling, or respiratory distress. A patient's comorbid illnesses must also be taken into account in the treatment plan.
A detailed examination of the head and neck should be performed, with particular focus on the oral cavity and oropharynx. This usually begins with a full inspection of the oral cavity, including thorough inspection of the teeth. Palpation of the oral cavity can help assess bony involvement, tongue fixation, and depth of involvement. Deviation or fixation of the tongue suggests involvement of extrinsic muscles of the tongue. Bimanual palpation can help assess the depth of tumor invasion into musculature of the tongue and floor of the mouth. A thorough palpation of the neck is important to assess regional nodal disease.
Imaging can complement the physical examination in determining the extent of disease. A chest x-ray should be performed to exclude lung metastases or a second primary cancer. CT is the modality most commonly used to determine the extent of soft tissue and bony involvement and occult disease in the neck (Fig. 41.13). CT may be used to determine the extent of invasion into the deep musculature of the tongue and adjacent structures. Moreover, CT is a valuable modality for visualizing invasion of the mandible, palate, and pterygopalatine fossa. If CT scanning is not available, then panoramic radiographs can be used to demonstrate mandibular invasion. MRI may be used in case of contrast allergy or a lesion that is not well visualized on CT. For instance, MRI may be used if a patient has significant dental
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artifact that obscures visualization of the primary tumor on CT. MRI provides excellent definition of tumor involving the tongue and is a good modality for evaluating the possibility of perineural spread. Ultrasound may be used to screen for enlarged lymph nodes that are not clinically detectable. In experienced hands, the accuracy of ultrasound when combined with fine needle aspiration may be superior to CT or MRI for staging the neck (118). Positron emission tomography (PET) and CT/PET are emerging technologies. Their greatest utility in head and neck cancer to date appears to be in identifying distant metastases and detecting persistent or recurrent disease. Reports have indicated that the overall sensitivity and specificity of PET may be equivalent or superior to CT and MRI for evaluating persistent or recurrent disease, particularly in patients who have received previous radiotherapy (5,36). PET/CT may improve the anatomic localization of abnormalities identified on PET and decrease the number of equivocal PET findings (94).
Clinical Staging
The American Joint Committee on Cancer has established a staging system for cancer of the oral cavity (Table 41.2). The staging guidelines apply to all forms of carcinoma (45). Nonepithelial malignancies are not included in the staging system.
General Management
Surgical resection, radiation, chemotherapy, or combined modality approaches are classical treatment options for patients with cancers of the oral cavity. The choice of treatment modality, either singly or in combination, depends on the stage and size of the tumor and relevant patient factors such as toxicity, performance status, comorbid disease, and convenience. Broadly speaking, single modality treatment (i.e., surgery or radiation) is preferred for early stage, T1 or T2 lesions. The control rates are generally the same for early stage lesions with either modality alone. For more advanced lesions a combined modality treatment approach is preferred.
In general, the choice for initial treatment of early stage oral cavity cancer is surgical resection. Surgical resection is expeditious, convenient, and often associated with modest morbidity. Radiation therapy may require both external beam and interstitial treatment for optimal therapeutic effect. A course of radiation can require several weeks of daily therapy followed by an interstitial implant. Moreover, the risk of associated xerostomia, osteoradionecrosis, and need for fluoride treatment may render radiation therapy a less attractive choice for single modality therapy. Nevertheless, for patients who are at significant surgical risk or in whom surgical resection would result in significant functional loss, radiation therapy offers a good alternative for definitive treatment.
For patients with advanced lesions of the oral cavity a combined modality approach is generally recommended. The timing of radiation, before or after surgery, has been a matter of some debate. There are advantages and disadvantages to either approach. The preponderance of data and practice pattern suggests that postoperative radiation is usually preferred. Further, there is emerging data that for selected patients with high-risk pathologic features, the addition of concurrent chemotherapy during the postoperative radiation treatment course may
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further augment tumor control rates provided the chemotherapy can be tolerated (7,21,26). High-risk features commonly include advanced T stage, multiple positive nodes, extracapsular tumor spread, positive resection margins, and perineural invasion (7,21).
Surgical Management
Cancer of the oral cavity is most commonly treated surgically when the disease is in its early stages (18). Since successful treatment of oral cavity carcinoma relies on effective management of the regional lymphatics as well as the primary cancer, the neck should be addressed in treatment planning. Elective neck treatment is often used for management of the clinically node negative patient with oral cancer, and therapeutic neck dissections are performed for patients with clinically apparent nodal disease. Postoperative radiation or chemoradiation is administered to those patients with pathologic evidence of extensive nodal disease and/or extracapsular spread. Because of the high occult metastatic rate for many cancers, elective neck treatment is encouraged in all but the earliest stages of primary site disease.
Surgical approaches to cancers of the oral cavity may either be transoral, transcervical (pull-through), or alternatively, via mandibulectomy, which is sometimes necessary to obtain the exposure required to achieve adequate margins. In cases where the mental or alveolar nerve is involved with tumor, the nerve should be proximally resected and analyzed microscopically. A tracheotomy is often necessary to maintain a patent airway because of the large amount of oral edema resulting from extensive resection and placement of myocutaneous flaps in the oral cavity.
Tumors that approximate the gingiva should be resected with the gingiva and periosteum as an additional deep margin, while those that appear to involve the periosteum should be resected with an additional deep margin of bone. This last procedure is termed a marginal mandibulectomy. Depending on the extent of tumor involvement, this may involve resection of a bicortical rim of bone at the upper aspect of the alveolus (rim mandibulectomy), or alternatively selective removal of the inner cortex using a vertical or oblique resection (sagittal mandibulectomy). It is commonly recommended to leave at least a 1-cm thick segment of bone inferiorly following a rim mandibulectomy to reduce the risk of pathologic fracture. Those lesions that directly invade bone should be resected with a segment of bone. This often requires soft-tissue or osseous reconstruction of the resected bone segment.
Regarding reconstruction after tumor resection, small surgical defects may not require reconstruction and therefore are often allowed to heal by secondary intention. Larger defects may be reconstructed by primary closure, skin graft, regional flap, or free tissue transfer from different sites. Goals of reconstruction are to replicate the function and appearance of the resected tissue. Urken et al. (115) have developed a systematic approach to functional reconstruction of the oral cavity. Their approach to reconstruction is based on the extent and functional status of the residual tongue and the presence or absence of an associated mandibulectomy.
Split thickness skin grafts are often used for reconstruction and are usually most expedient and efficacious for small defects. Larger defects may require a local or regional flap. Small intraoral defects can be reconstructed effectively with palatal, tongue, and buccal mucosa flaps but usually at the cost of decreased function. Regional flaps that are used in the reconstruction of the oral cavity include the pectoralis major flap, trapezius flap, and latissimus dorsi flap. Continuing developments in microvascular surgery have allowed for head and neck reconstructive surgeons to perform free tissue transfer to reconstruct oral cavity defects. Disadvantages of this procedure include the complexity of the technique and the increased surgical time. The free flaps most commonly utilized in the oral cavity are the radial forearm flap, the anterolateral thigh flap, the rectus abdominis flap, and the fibula flap.
Total glossectomy defects are well suited for free flap reconstruction. Reconstruction of the mandible often requires free flaps that contain bone and soft tissue such as the fibula flap, the iliac crest flap, and the scapular flap. Compared to reconstruction plates free flaps also allow the potential for a sensate flap through neural anastomosis. A sensate flap may result in improved swallowing and speech function, but few studies have unequivocally demonstrated an improvement in these functional outcomes (6,112,113,114,116,117).
Radiation Therapy
General Principles
For early lip, oral tongue, and floor of the mouth tumors, radiation therapy is an effective means of securing tumor control (50). Acceptable control rates have been achieved with brachytherapy alone or with a combination of brachytherapy and external beam radiation. Early work indicates that the success rate of radiotherapy is higher if some or all of the treatment is administered with brachytherapy (42,44). Decroix and Ghossein (28) reported outcomes in 602 patients with cancer of the oral tongue treated with radium implantation or implantation plus external beam radiation. In this series, recurrence at the primary site or at the primary site and neck was 14% and 22% for T1 and T2 lesions, respectively. The Royal Marsden Hospital reported local control rates of 90% at 5 years for T1 and T2 tumors treated with interstitial radiation with or without external beam radiation (27). Pernot et al. (84) reported local control rates of 96% for T1, 85% for T2, and 64% for T3 lesions of the oral cavity treated with brachytherapy and neck dissection. In this series, local regional control rates were 83%, 70%, and 44%, respectively. Retrospective studies suggest that control rates at the primary site of early oral cavity lesions treated with brachytherapy alone or a combination of brachytherapy plus external beam radiation range from approximately 70% to >95% (27,28,83,84). Involvement of the mandible is a contraindication to definitive radiotherapy because it compromises control and increases the risk of osteoradionecrosis.
Intraoral cone, like interstitial brachytherapy, is a localized radiation therapy technique that has been used to boost the dose to the primary tumor in the oral cavity. Institutions with significant experience with this technique have reported results that rival those obtained by interstitial brachytherapy (122,123). Either technique for boosting the primary tumor has resulted in improved outcomes compared to high-dose radiation therapy alone (34,125). In general, external beam radiation therapy followed by either technique is preferable over radiation therapy alone. As with all specialized procedures, the skill and experience of the radiation oncologist is of critical importance to the successful delivery and outcome of interstitial radiation or intraoral cone therapy.
The outcomes for advanced lesions of the oral cavity (T3 and T4) are less than satisfactory with either surgery or radiation alone. In most advanced stage cancers single modality therapy is inferior to combined modality therapy (44,97,119). Adjuvant radiation therapy can be delivered preoperatively or postoperatively (97,122). Although each strategy has potential advantages and disadvantages, postoperative radiation therapy is generally preferred. Notable disadvantages of preoperative radiation therapy include a delay in definitive surgical treatment and limitations on the dose of radiation that can be delivered due to the risk of wound complications after surgery. Postoperative radiation treatment carries the advantage of no
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dose limitation, no delay in the implementation of surgical resection, and complete pathologic staging of the tumor. However, it must be borne in mind that postoperative wound complications may delay the implementation of postoperative radiation, and the regional hypoxia that can accompany the postoperative state may diminish the effectiveness of radiation compared to that achievable under conditions of full oxygenation.
Adjuvant Radiation
Although surgery has emerged as the preferred initial treatment approach for the majority of patients with tumors of the oral cavity, adjuvant radiation is commonly recommended to enhance the likelihood of locoregional tumor control. Robertson et al. (92) conducted a phase III study in the United Kingdom of 350 patients with T2-4/N0-2 oral cavity or oropharyngeal cancers comparing surgery and postoperative radiation versus radiation alone. Because a difference in survival was identified, the study was closed early. The authors found that after 23 months, overall survival, cause-specific survival, and local control were all improved on the surgery plus radiation arm. Indications for postoperative radiation therapy include multiple cervical metastases, positive or close margins, extracapsular extension, perineural invasion, advanced T stage, and suspicion of mandibular cortical involvement. In regards to buccal mucosa cancers, Mishra et al. (74) conducted a prospective randomized trial of surgery with or without adjuvant radiation 6 weeks after surgery. They reported a 30% absolute improvement in disease-free survival, although there was no difference in overall survival with the use of adjuvant radiation therapy.
Recently, there has been interest in the evaluation of postoperative chemoradiation for patients with high-risk pathologic features. The results of two randomized trials suggest that postoperative chemoradiation may be beneficial for improving local–regional control and disease-free survival among selected patients with specific high-risk features (7,21).
Neoadjuvant Therapy
At the current time, neoadjuvant radiation and chemotherapy remain largely experimental for cancer of the oral cavity. The use of preoperative chemotherapy has been studied in at least two randomized trials. Licitra et al. (60) conducted a phase III study of 195 patients with T2-4 (>3 cm) N0-2 squamous-cell carcinoma of the oral cavity and randomized patients to surgery alone versus three cycles of cisplatin and 5-fluorouacil (5-FU) followed by surgery. The authors found no difference in overall survival but did comment on the possibility of neoadjuvant chemotherapy as potentially improving resectability and reducing the need for adjuvant radiation therapy. In a similarly designed trial, Volling et al. (120) also reported no difference in overall survival with the use of neoadjuvant chemotherapy, although there was an improvement in disease-free survival.
Preoperative chemoradiation has been studied prospectively by Mohr et al. (76). The authors randomized 268 patients with T2-4/N0-3 oral cavity and oropharyngeal cancers to either preoperative chemoradiation with cisplatin versus surgery alone. Results of this study revealed an improvement in overall survival and local control with the use of preoperative therapy. This regimen, however, has not shown common adoption in other centers around the world.
Radiation Techniques
Carcinoma of the oral cavity has traditionally been treated with opposed lateral fields, using either two-dimensional or three-dimensional CT-based techniques. During simulation and treatment patients are commonly immobilized with a thermoplastic mask. Patients are placed in supine position with a bite block (for oral tongue and floor of mouth cases) to depress the tongue away from the palate (Fig. 41.14); some institutions use a cork and tongue blade for this purpose. For patients with a short neck, the shoulders are depressed by having the patient pull on a tensioning device looped beneath the feet. Generally, the oral cavity tumor bed and upper echelon lymph nodes are included within the initial lateral fields (Fig. 41.15). The upper border of the field is positioned to provide a 1.5- to 2-cm border on the tumor bed in an attempt to partially spare parotid glands and hard palate if possible without compromising coverage of the tumor bed and regional lymphatics. The inferior border of the field resides at approximately the thyroid notch, just above the true vocal cords. The posterior border is set at the mid-vertebral body level if level V nodal coverage is not required. The nodal volume should include level Ia-Ib, II, and III. For patients with more advanced neck disease or neck risk or positive level V lymph nodes, where the posterior chain requires radiation, the initial fields should be set behind the C1 vertebral body spinous process. The portals are then reduced at approximately 45 Gy to spare high dose to the spinal cord. If patients harbor cervical lymph node metastases, or high-risk disease, then the lower neck will also be treated. In this case, a single half-beam-blocked anteroposterior field is matched to the inferior border of the opposed lateral fields at the level of the thyroid notch (Fig. 41.16). An anterior larynx block is used, which protects not only the central larynx from unnecessary radiation dose, but also protects against spinal cord overdose due to three-field overlap.
Megavoltage beams with an energy range between 4 and 6 MV are most suitable for treatment of cancers involving the oral cavity. Cobalt-60 (similar average energy to that from 4 MV linear accelerators) remains a very acceptable radiation delivery unit for cancers in this region owing to the small lateral separation distances in the head and neck area. When higher energy beams are used, bolus material may be necessary to bring dose to the surface as required for tumors that extend to the skin. This is particularly important in patients with large volume nodal disease or extracapsular extension where particular attention should be paid to adequate dosing of superficial tissues. Tissue compensating filters should be used with opposed lateral fields when the variation of the separation is >3 cm. All fields should be treated daily and at least 5 treatment days per week.
In recent years, there has been increasing use of intensity-modulated radiation therapy (IMRT) for the treatment of head
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and neck region tumors (Fig. 41.17). With regard to oral cavity cancer, IMRT offers the opportunity to diminish normal tissue toxicities, including damage to major salivary glands (xerostomia) and to the mandible (osteoradionecrosis) (23,110,129). Dosimetric analysis of radiation dose to the parotid glands with evaluation of resultant salivary function suggests that limiting mean parotid dose to <26 Gy is associated with improved postradiation salivary function (31). Ideal candidates for IMRT include patients with T1-3 primary lesions with ≤N2b neck disease. In light of the steep dose gradients that often accompany IMRT plans, successful delivery is dependent on accurate and reproducible localization and immobilization. At several centers, an optically guided localization system is used to enhance daily treatment precision for IMRT delivery. Tomotherapy, which involves the helical delivery of intensity modulated radiation, enables a high degree of target conformality coupled with the capacity for diagnostic CT scanning, thereby allowing image guidance for adaptive radiotherapy and daily setup verification (39,48,101).
Dose and Fractionation
When postoperative radiation is used for oral cavity cancer, the most common dose fractionation in the United States is 1.8 to 2.0 Gy per day. Dissected tissues that harbored the original tumor should generally receive on the order of 60 Gy. However,
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for close or positive microscopic margins or extracapsular nodal extension, a 4- to 6-Gy localized boost should be considered. If there is gross residual disease, either further surgical resection or focal boosting up to 70 Gy is advisable. Regions of somewhat lesser risk (i.e., clinically or pathologically uninvolved necks) should receive on the order of 50 to 54 Gy.
When definitive radiation is used for oral cavity cancer, boosting the primary tumor with either interstitial implantation, submental, or intraoral cone therapy can result in increased tumor control and decreased complications, particularly osteoradionecrosis (34). When external beam radiation therapy is used as the sole treatment modality, even small lesions that cannot be excised or treated with brachytherapy require doses in the range of 66 Gy in 2-Gy fractions for reliable control. For larger tumors, improved local control rates are likely to be achieved with doses ≥70 Gy, but there is an increasingly significant price to pay in terms of normal tissue toxicity for doses in this range.
Altered Fractionation
It is well appreciated that head and neck tumors are rapidly proliferating. There has been significant interest in the use of intensified radiation fractionation schedules to counter rapid tumor cell repopulation as a means of improving outcome in head and neck cancer patients treated with radiation. Altered fractionation regimens such as hyperfractionation or accelerated fractionation should be considered for patients being treated with radiation alone, as this approach has been demonstrated to improve the likelihood of locoregional tumor control (85). The Radiation Therapy Oncology Group's (RTOG 90-03) altered fractionation randomized trial comparing conventional fractionation to hyperfractionation, split-course, and concomitant boost technique demonstrated a significant improvement in disease-free survival for the hyperfractionation and concomitant boost arms (43). These altered fractionation regimens were associated with higher incidence of grade 3 or worse acute mucosal toxicity, but no significant difference in overall toxicity at 2 years following completion of treatment. However, oral cavity carcinoma constituted a minority of cases enrolled in these studies.
Brachytherapy
Historically, brachytherapy has played an important role in the treatment of oral cavity carcinoma. Brachytherapy has been used to boost the primary site in the oral cavity before or following external beam radiation (Fig. 41.18). This technique has also been used as a sole modality in the treatment of selected (early stage) tumors of the oral cavity with good results (58,83,84). When brachytherapy is used as a sole treatment modality, doses of 65 to 75 Gy are commonly prescribed over 6 to 7 days. Traditionally, radiation has been delivered using low-dose rates of 0.4 to 0.6 Gy per hour to the target volume (75,108). However, there has been recent interest in high-dose rate (Fig. 41.19) and pulsed-dose rate techniques (68,93), although there is no compelling evidence that these techniques are superior to traditional low-dose rate radiation in the treatment of head and neck cancer. Many techniques for brachytherapy in the oral cavity have been described (73,86). Brachytherapy can be accomplished with either rigid cesium needles or with iridium-192 (192Ir) sources afterloaded into angiocaths. The most common technique is afterloading with 192Ir (124). Guide needles can be inserted either free-hand or with the aid of a custom template to help maintain optimal source spacing.
Depending on the size of the lesion a single plane, double plane, or volume implant can be used to cover the tumor with a 1-cm margin. For tumors <1 cm in thickness, single plane implants are adequate. Surface mold radiation can also be considered for small tumors <1 cm depth or superficial lesions of the lip, hard palate, lower gingiva, and floor of the mouth. However, when lesions exceed 2.5 cm, it is difficult to avoid significant cold spots in the implant volume. For this reason, it is recommended that for lesions larger than 2.5 cm part of the treatment be given with external beam radiation to supplement the dose to the cold spots. In this setting, a combined treatment plan typically gives 50 Gy over 5 weeks with external beam
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radiation followed by 30 Gy with a brachytherapy implant. What must be borne in mind is that as tumors get too close to the mandible or are large in volume, the risk of osteoradionecrosis increases (64).
Over the past decade or more, stepwise improvements in reconstructive surgery techniques have diminished the practice frequency of brachytherapy in the treatment of oral cavity carcinoma. In addition, a diminishing percentage of radiation oncologists remain highly skilled and experienced with the requisite implant techniques. Finally, the steady advancement of highly conformal external beam techniques (IMRT, tomotherapy) has contributed to less frequent practice of brachytherapy in head and neck cancer overall. The identical comments parallel the use of intraoral cone radiation treatment described further in the section below.
Intraoral Cone
The intraoral cone is another delivery tool to enable boosting of radiation dose to sites within the oral cavity while avoiding
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direct dose to the mandible (Fig. 41.20). This technique is generally best suited for anterior oral cavity lesions in edentulous patients. However, palatal arch sites can be targeted with the intraoral cone as well. Treatment with intraoral cone involves either 100 to 250 kilovolt (peak) (kvp) x-rays or electron beams in the 6 to 12 MeV range (73,122,123). Lesions up to 3 cm are amenable to treatment with intraoral cone as long as they are accessible. Intraoral cone therapy requires careful daily positioning and verification by the physician. For this purpose the device is equipped with a periscope to visualize the lesion. The cone abuts the mucosa and is centered directly over the lesion. Intraoral cone treatment should take place prior to external beam radiation so that the lesion can be adequately visualized. A major advantage of cone therapy is that it is highly focal to the tumor bed but noninvasive. Hence, when available, for suitable lesions, it may be preferred over brachytherapy. However, as noted for brachytherapy delivery, operator experience and dedication are essential to optimize outcome.
Chemotherapy and Radiation
The application of chemotherapy to the treatment of head and neck cancer dates back to the 1960s. Over the decades the role of chemotherapy has advanced from initial use only in the recurrent or metastatic setting to active current use in the definitive treatment setting. There are a number of studies that demonstrate a benefit of concurrent chemotherapy administration in the definitive treatment of head and neck cancer with radiation (1,10,15,29,71,107,127). Although these trials vary with respect to radiation dose, fractionation schedule, and chemotherapy regimen, they have in common a randomized comparison between radiotherapy and radiotherapy plus chemotherapy. The advantage of concurrent chemotherapy with radiation has been further examined in the context of several meta-analyses (11,32,78,87). These meta-analyses generally identify a small overall survival benefit for the use of chemotherapy on the order of 1% to 8% (49). Summary analyses suggest no significant survival benefit for the use of neoadjuvant and adjuvant chemotherapy, but do suggest a clear benefit for the use of concurrent chemoradiation. However, in many of the randomized studies comparing radiation alone to chemoradiation, oral cavity patients are either excluded or make up only a small proportion of the study population.
Several recent studies have focused on the use of chemoradiation in patients with high-risk pathologic features following initial surgery. Cooper et al. (21) reported the results of a randomized study in North America comparing radiation alone (60 to 66 Gy) to chemoradiation (same radiation dose plus three cycles of 100 mg/m2 cisplatin) in patients with head and neck carcinoma demonstrating high-risk features after gross total resection. High-risk disease was defined as any or all of the following: two or more involved lymph nodes, extracapsular extension of nodal disease, and microscopically involved resection margins. This study demonstrated a benefit in local–regional control and disease-free survival for the chemoradiation arm, but no overall survival benefit was appreciated. A parallel study in Europe by Bernier et al. (7) randomized patients to essentially equivalent treatment arms following head and neck cancer surgery. Eligibility criteria included patients with pathologic T3 or T4 disease (except T3/N0), or patients with any T-stage disease with two or more involved lymph nodes, or patients with T1-2 and N0-1 disease with unfavorable pathologic findings (extranodal spread, positive margins, perineural involvement, or vascular embolism). Local control, progression-free survival, and overall survival were superior for patients on the chemoradiation arm. These studies suggest that the addition of chemoradiation following surgery may be beneficial in selected patients with high-risk head and neck cancer, although with increased toxicity profiles.
Dental Care
Prior to the initiation of head and neck radiation a careful oral and dental evaluation, including a panoramic radiograph, should be performed. Dentition in poor condition should be identified and considered for extraction to minimize the subsequent risk of osteoradionecrosis. Specifically, those teeth that will reside within the high-dose radiation volume that demonstrate significant periodontal disease, advanced caries, abscess formation, or are otherwise in a state of disrepair should be extracted. In addition, impacted teeth, unopposed teeth, and teeth that could potentially oppose a segment of a resected jawbone should be considered for extraction if they are anticipated to reside within the high-dose radiation treatment volume. Extraction of marginal teeth should also be considered in patients who are deemed unable to maintain adequate oral hygiene.
Radiation can induce several chronic effects in the oral cavity that warrant routine surveillance. Radiation can impair bone healing and diminish the capacity for successful recovery following trauma or oral surgery. For this reason, elective oral surgical procedures including extractions must be very carefully considered after radiation. Escalation of dental caries deriving from xerostomia following radiation is well recognized (Fig. 41.21). Radiation of the major salivary glands changes the nature of salivary secretions (121), which can increase the
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accumulation of plaque and debris, reduce salivary pH, and reduce the buffering ability of saliva (55). This creates an environment in the oral cavity, which predisposes patients to caries. During a course of radiation to the oral cavity, simple techniques such as the use of custom molds to absorb electron backscatter can diminish hot-spot mucositis from dental fillings and improve treatment tolerance (Fig. 41.22). Attention to oral hygiene with frequent dental follow-up examinations and cleanings, daily fluoride therapy (Fig. 41.23), flossing, and brushing should be an integral component of the education and postradiation care of patients who undergo radiation to the oral cavity.
Prognostic and Predictive Factors
The most significant prognostic factor for outcome in oral cavity carcinoma is the presence of cervical metastases (81). In patients with positive cervical metastases the 5-year survival is reduced by approximately 50% from that in the absence of metastases (53). The prognosis diminishes further when patients harbor multiple levels of nodal involvement or extracapsular extension (ECE). In a retrospective review, Myers et al. (81) found that 5-year disease-specific and overall survival rates for pathologically N0 patients were 88% and 75%, respectively; these decreased to 65% and 50%, respectively, if patients were node positive but without evidence of ECE. Patients who were node positive with evidence of ECE had 5-year disease-specific and overall survival rates of 48% and 30%, respec-tively.
Several histopathologic factors in the primary lesion are associated with adverse prognosis. Tumor thickness and depth of invasion have been shown to confer a higher risk of regional metastases (18). Perineural invasion has been correlated with cervical lymph node metastases, extracapsular extension, and diminished survival (8,35,105). Microvascular invasion has also been correlated significantly with cervical lymph node metastases (19,67). However, lymphatic invasion has not been correlated significantly with cervical lymph node invasion (18). The
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prognostic significance of grade has also been evaluated (3). Because of the wide variation in pathologic interpretation, it is difficult to discern the independent value of histologic grading as a prognostic or predictive value (18).
Subsite-Specific Treatment and Results
Lip
Early stage carcinoma of the lip can be managed with surgery or radiation therapy. However, surgery is generally preferred for small tumors (<2 cm). Although the local control of T1 and T2 squamous cancers of the lip is excellent with surgical resection, disruption of the oral sphincter provided by the orbicularis muscle can lead to oral incompetence if not properly reconstructed. Therefore, a number of reconstructive methods have been developed to help preserve oral sphincteric function even following large excisions for T3 and T4 lesions. For these larger lesions, surgery followed by radiotherapy remains a standard therapy.
When primary radiotherapy is used to treat lip cancer, the target volume should include the primary tumor plus a 1.5- to 2-cm margin. For early stage lesions, photons in the orthovoltage range (100 to 200 keV) or electrons may be used. The electron energy should be chosen based on the thickness of the lesion (commonly 6 to 9 MeV). Effort should be made to shield the underlying gum, dentition, and mandible as appropriate. This can be accomplished with the use of oral shields or cerrobend stents. The recommended dose is 50 Gy in 4.5 to 5 weeks for smaller lesions and 60 Gy in 5 to 6 weeks for larger lesions. Some institutions have used an approach where external beam radiation is given to approximately 40 to 50 Gy followed by a brachytherapy boost, or smaller lesions are treated by primary brachytherapy alone. An important consideration in managing lip cancer is the risk of regional metastatic disease. Generally, the risk of regional lymph node metastatic disease for T1 and T2 cancers of the lip is lower than for stage-matched tumors of other oral cavity sites. Thus, elective neck dissection is recommended for patients with T3 and T4 carcinomas of the lip; however, it may not be warranted for all T1 and T2 lesions. Some institutions have used a “moustache field” for elective irradiation of the perifacial lymphatics (approximately 50 Gy) for more advanced upper lip lesions (2). Sentinel lymph node biopsy may prove to be useful in the management of patients of node-negative lip cancers, but further clinical investigation in this area is needed.
Oral Tongue
Although primary radiation therapy and surgery are potential treatment options for carcinoma of the oral tongue, most oral tongue cancers in the United States are treated surgically (18). Surgical resection and reconstruction as appropriate is generally preferred for medically operable patients. Postoperative radiation therapy is recommended for patients with large primary tumors (T3, T4), close or positive surgical margins, evidence of perineural spread, multiple positive nodes, or extracapsular extension (2). Postoperative chemoradiation should be considered for patients with adverse risk factors who are able to tolerate combined modality treatment (7,21). Primary radiotherapy techniques can be used for patients who refuse or are unable to tolerate surgery.
Superficial T1 lesions can be treated with brachytherapy alone. Commonly, 192Ir temporary implants are used to deliver 50 to 60 Gy with dose rates of 40 to 60 cGy per hour. For infiltrating T1 or T2 lesions, a combined approach using external beam and a brachytherapy or intraoral cone boost should be considered. More advanced lesions should be treated with an approach combining surgery and radiation therapy. Postoperative treatment should include the site of primary tumor, dissected neck, and draining lymphatics. Opposing lateral fields are used to encompass the tongue and upper neck bilaterally, and this volume should be treated to 50 to 54 Gy (see Fig. 41.12A and Table 41.1). High-risk areas (primary surgical bed, positive/close margins, extracapsular extension, perineural spread) should receive additional boost treatment up to 60 to 66 Gy.
Surgical approaches to oral tongue cancers can either be transoral, transcervical, or alternatively via mandibulectomy to obtain the exposure necessary to achieve adequate margins. Partial glossectomy is the most common procedure performed for oral tongue cancers, and the extent of resection depends on the size and growth pattern of the tumor, as some lesions are relatively infiltrative while others may be more exophytic. Since the tongue is essentially comprised of skeletal muscle covered by mucosa, the tissue is extremely elastic, and wide margins are encouraged at the onset of resection to avoid retraction of muscle fibers with microscopic tumor cells that could serve as a source of local recurrence.
Total glossectomy may be indicated for extensive tumors or those that involve the intrinsic tongue musculature. Total glossectomy, even with reconstruction, can result in difficulty with deglutition and maintenance of an adequate airway. Aspiration may be a chronic problem, and, thus, laryngectomy may be necessary in some cases. However, properly selected patients with adequate postoperative rehabilitation can be treated with total glossectomy without laryngectomy. If the larynx is preserved, laryngeal suspension and palatal augmentation may help with the rehabilitative efforts.
Tumor size and depth of invasion are currently the most reliable indicators for predicting cervical metastases in patients with oral tongue squamous-cell carcinoma. Because of the high risk of nodal metastases the neck should be addressed either with surgery or radiation in all but the earliest tumors of the oral tongue. Patients with small oral tongue cancers should be considered for neck therapy, particularly if the primary tumor exhibits extension onto the floor of mouth or there is increased tumor thickness. Treatment of the clinically negative neck is most often accomplished by supraomohyoid neck dissection. Elective neck dissection appears to result in better overall cancer outcome than observation. Potential pitfalls of observation include a salvage rate of only one-third for patients who do not undergo elective neck dissection along with resection of the oral cavity primary. For patients with a clinically and radiographically N0 neck, with well-lateralized disease, or those who do not undergo neck dissection, 50 to 54 Gy should be considered to the ipsilateral neck as elective nodal irradiation (Fig. 41.16).
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Patients with advanced lesions and high-risk disease (particularly with multiple positive nodes) should receive radiation treatment to the bilateral neck.
Floor of the Mouth
Early stage floor of the mouth cancer can be treated effectively by radiation therapy or surgery. However, surgery is usually preferred in patients who are medically operable because proximity of the tumor to the mandible confers a significant risk of radiation-induced ulceration and osteoradionecrosis. Small lesions of the floor of the mouth are most commonly resected transorally. The surgical defect can be left to heal by granulation or reconstructed with a split thickness skin graft or local flap. Advanced stage floor of the mouth cancers are usually managed by a combination of surgery and radiation or chemoradiation.
Small (T1 and T2) lesions may be treated with a combination of external beam radiation and boost with interstitial implant or intraoral cone. For lesions that are very close to the mandible, brachytherapy is contraindicated because of the risk of osteoradionecrosis. Infiltrative lesions that are tethered to the mandible and advanced lesions following surgical resection should receive postoperative radiation. Portals for postoperative treatment are similar to that for oral tongue carcinoma. Opposing lateral fields are used to encompass the oral cavity tumor bed and upper neck bilaterally, and this volume is commonly treated to 50 to 54 Gy. High-risk areas (primary surgical bed, positive/close margins, extracapsular extension, perineural spread) may receive additional boost treatment up to 60 to 66 Gy.
In the surgical management of floor of the mouth cancer, special attention should be paid to mandibular invasion. A cancer that appears to involve only the periosteum or that only superficially invades the mandible can be removed via a transoral or transcervical approach in which a marginal mandibulectomy is performed. However, segmental mandibulectomy may be necessary for patients with a limited mandibular height when there is no direct bone invasion, because marginal mandibulectomy may leave these patients with insufficient bone, placing them at high risk for radionecrosis or pathologic fracture. A full thickness segmental resection may be necessary if there is frank bone invasion. For advanced cancers, resection of the anterior arch of the mandible may be necessary. Defects of the anterior segment of the mandible require reconstruction with bone, usually with a free fibular or iliac crest graft.
Management of the neck is similar to that for other tumors of the oral cavity. Patients with lesions <2-mm thick with no adverse pathologic factors and a clinically and radiographically negative neck may be observed after primary resection and observation. Otherwise most N0 patients should receive either selective neck dissection or radiation therapy. Patients with advanced lesions and high-risk disease (particularly with multiple positive nodes) should receive radiation treatment to bilateral necks.
Hard Palate and Upper Alveolar Ridge
Tumors of the hard palate are quite rare, accounting for only 0.5% of all oral cancers in the United States. Most carcinomas manifest as a granular superficial ulceration of the hard palate. Initial growth tends to be superficial, although these tumors can extend through the periosteum of bone into regions adjacent to the oral cavity, such as the paranasal sinuses and floor of the nose. Although radiation can be used to treat carcinomas of this site, surgery is preferred. Postoperative radiation therapy should be delivered when there are adverse features; that is, close/positive margins, perineural extension, vascular invasion, high-grade histology, multiple positive nodes, or extracapsular extension. The radiation field should encompass the entire surgical bed. In most cases it is necessary to treat with opposed lateral fields to cover the volume at risk. However, for well-lateralized lesions of the upper alveolar ridge, ipsilateral radiation with a wedge pair may be adequate. Conformal treatment techniques can also be used to tailor the radiation coverage to the high-risk tissue bed and draining lymphatics as appropriate.
Wide local excision may be adequate to obtain surgical margins. However, infrastructure maxillectomy may in some cases be necessary. For tumors that extensively involve the adjacent bony and soft tissue structures a total maxillectomy, with or without orbital exenteration, may be required. A defect in the maxilla results in lack of oral/nasal separation that can impair the ability to speak and swallow effectively. An obturator with or without a skin graft is the most common method used to restore oral/nasal separation. The obturator is commonly fabricated from a synthetic polymer and provides oronasal separation that can yield improved speech and swallowing function. Regional pedicled flaps and free-tissue transfers may provide alternatives to obturation. However, their use is somewhat controversial for reconstruction of palatal defects since these nonremovable flaps may mask local recurrences that can be more readily identified in patients whose defects are obturated.
Elective treatment of the neck is controversial for hard palate region tumors. Although some series have shown lower rates of occult metastases for palatal tumors when compared to other oral cavity sites, preoperative imaging should be performed to evaluate for the presence of metastases to the retropharyngeal nodes since these are difficult to evaluate on clinical examination and are at some risk for spread from primary palatal tumors.
Retromolar Trigone
Squamous-cell carcinoma of the retromolar trigone is uncommon, and the true incidence is difficult to determine since these cancers often involve both the retromolar trigone and adjacent sites, thereby making it difficult in some cases to identify the original tumor epicenter. Cancers of the retromolar trigone may be advanced at presentation because only a thin layer of soft tissue overlies the bone in this region and invasion of the underlying bone may occur early. In addition, there are multiple pathways for spread from this site including the buccal mucosa, tonsillar fossa, glossopharyngeal sulcus, floor of the mouth, base of the tongue, hard and soft palate, masticator space, and maxillary tuberosity. As patients tend to present with advanced disease of the retromolar trigone, many have regional metastases at the time of presentation.
Early stage T1 and T2 cancers can be treated equally effectively with surgery or radiation with primary control rates for T1 and T2 tumors of 92% and 88%, respectively. For more extensive superficial lesions that extend to involve the soft palate or tonsillar complex but do not invade bone, radiotherapy may be a better treatment option, since broad resection of the palate can result in poor speech and swallow outcomes. Well-lateralized lesions of the retromolar trigone can be treated by ipsilateral mixed beam techniques or angled wedge techniques.
Stage III and IV lesions commonly require combined surgery and radiation. The resection of advanced cancer of the retromolar trigone usually requires a composite resection of soft tissue and bone. A limiting factor for the achievement of adequate surgical resection margins for tumors in this area includes extension of tumor posterosuperiorly into the pterygopalatine fossa and into the base of skull.
Buccal Mucosa
Verrucous carcinoma accounts for <5% of all oral cavity carcinomas, occurs most often in the buccal mucosa, has a more
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favorable prognosis, and is considered a low-grade malignancy. Surgical resection remains the preferred mode of treatment for primary lesions of the buccal mucosa. Adjuvant radiation treatment is usually not indicated. Since verrucous carcinomas rarely metastasize, elective neck dissection is often not indicated for patients with this disease. Careful pathology review with clinical correlation is important in the categorization of verrucous carcinomas, as this diagnosis can influence subsequent treatment recommendations.
Squamous-cell carcinoma of the buccal mucosa can be an especially aggressive cancer of the oral cavity, as buccal cancers have multiple potential routes of spread to adjacent areas in the head and neck. Posteriorly, they can extend to involve the pterygoid muscles, and superiorly, they can grow to involve the alveolar ridge, palate, or maxillary sinus. The majority of patients have cancer that extends beyond the buccal mucosa. Metastasis to the cervical lymph nodes most commonly affects the submandibular nodes.
T1 and T2 tumors of the buccal mucosa can be managed with equal effectiveness by either surgery or radiation. Transoral resection is preferred and is most convenient for small lesions. Tumors approximating the gingiva should be resected with the gingiva and periosteum as an additional deep margin, while those that involve the periosteum should be resected with an additional deep margin of bone. Cancers that directly invade bone should be resected with a segment of bone. Larger tumors (T3 or T4) may require surgery combined with radiation therapy.
Management of Recurrent Disease
The appropriate management of recurrent oral cavity cancer depends largely on the extent of disease, the prior therapy administered, and whether the recurrences are local, regional, or both. Obviously, if there is distant disease recurrence, systemic therapy approaches will likely assume primary importance. In the case of small recurrences at the primary site for patients treated with primary excision only, further excision with or without postoperative radiotherapy is often recommended. For larger recurrences in patients who received radiation as part of their initial management, the rate of surgical salvage is quite low. In some cases, further resection may be considered for palliation or curative treatment attempt, particularly in the setting of a clinical trial. Systemic therapy, reirradiation, and palliative care are other options for this group of patients, and the risks and benefits of each should be discussed with the individual patient.
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